[ Evidence-Based Medicine ]

Therapy for Pulmonary Arterial Hypertension in Adults Update of the CHEST Guideline and Expert Panel Report

James R. Klinger, MD, FCCP; C. Gregory Elliott, MD, FCCP; Deborah J. Levine, MD, FCCP; Eduardo Bossone, MD, PhD, FCCP; Laura Duvall, PharmD, BCPS; Karen Fagan, MD; Julie Frantsve-Hawley, PhD; Steven M. Kawut, MD; John J. Ryan, MD; Erika B. Rosenzweig, MD; Nneka Sederstrom, PhD, FCCP; Virginia D. Steen, MD; and David B. Badesch, MD, FCCP

BACKGROUND: Pulmonary arterial hypertension (PAH) carries a poor prognosis if not promptly diagnosed and appropriately treated. The development and approval of 14 medi- cations over the last several decades have led to a rapidly evolving approach to therapy, and have necessitated periodic updating of evidence-based treatment guidelines. This guideline statement, which now includes a visual algorithm to enhance its clinical utility, represents the fourth iteration of the American College of Chest Physicians Guideline and Expert Panel Report on Pharmacotherapy for PAH. METHODS: The guideline panel conducted an updated systematic review to identify studies published after those included in the 2014 guideline. A systematic literature search was conducted using MEDLINE via PubMed and the Cochrane Library. The quality of the body of evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations Assessment, Development and Evaluation approach. Graded recom- mendations and ungraded consensus-based statements were developed and voted on using a modified Delphi technique to achieve consensus. RESULTS: Two new recommendations on combination therapy and two ungraded consensus- based statements on palliative care were developed. An evidence-based and consensus-driven treatment algorithm was created to guide the clinician through an organized approach to management, and to direct readers to the appropriate area of the document for more detailed information. CONCLUSIONS: Therapeutic options for the patient with PAH continue to expand through basic discovery, translational science, and clinical trials. Optimal use of new treatment op- tions requires prompt evaluation at an expert center, utilization of current evidence-based guidelines, and collaborative care using sound clinical judgment. CHEST 2019; 155(3):565-586

KEY WORDS: evidence-based medicine; guidelines; pulmonary arterial hypertension (PAH)

ABBREVIATIONS: 6MWD = 6-min walk distance; AHRQ = Agency for phosphodiesterase type-5 inhibitor; PH = pulmonary hypertension; Healthcare Research and Quality; CHEST = American College of Chest PICO = population, intervention, comparator, outcome; SSc-PAH = Physicians; COI = conflict of interest; ERA = endothelin receptor scleroderma-spectrum of disease and PAH; SSRI = selective serotonin antagonist; FC = functional class; FDA = Food and Drug Adminis- reuptake inhibitor; WHO = World Health Organization tration; GRADE = Grading of Recommendations, Assessment, AFFILIATIONS: From Brown University (Dr Klinger), Providence, RI; Development and Evaluation; HR = hazard ratio; IPAH = idiopathic Intermountain Healthcare and the University of Utah School of pulmonary arterial hypertension; MID = minimally important differ- Medicine (Dr Elliott), Murray, UT; University of Texas Health ence; PAH = pulmonary arterial hypertension; PDE5I =

chestjournal.org 565 Note on Shaded Text: In this guideline, shaded text with radiologists, cardiothoracic surgeons, transplant teams, an asterisk (shading appears in PDF only) indicates primary care, and other specialists. In addition, statements that are newly added or have been changed appropriate care may involve teams of allied health since the publication of “Pharmacologic Therapy for professionals, including advanced practice clinicians, Pulmonary Arterial Hypertension in Adults: CHEST nurse coordinators, respiratory therapists, exercise Guideline and Expert Panel Report” in 2014. Statements physiologists, social workers, pharmacists, among that remain unchanged since that edition are not shaded. others. Caregiver support, whether it be by family or The order of our presentation should not be interpreted as friends remain an integral part of the care team. the guideline panel’s order of preference for the use of These teams of physicians, and allied health these agents. professionals and caregivers are important components in centers with expertise in the diagnosis of PAH. Summary of Recommendations 1. We suggest that the severity of a PAH patient’s Remark: Further discussion of tools for evaluating disease be evaluated in a systematic and consistent disease severity and mortality risk and description of manner, using a combination of WHO FC, exercise centers of expertise is provided in the section entitled “ ” capacity, echocardiographic, laboratory and Pharmacologic Therapy for PAH in Adults. hemodynamic variables in order to inform Treatment Naive PAH Patients Without Symptoms therapeutic decisions (Ungraded consensus-based (WHO FC I) and Patients at Increased Risk for the statement). Development of PAH 2. We suggest that, whenever possible, all PAH 4. For treatment-naive PAH patients with WHO FC I patients be evaluated promptly at a center with symptoms, we suggest continued monitoring for the expertise in the diagnosis of PAH, ideally prior to the development of symptoms that would signal disease initiation of therapy (Ungraded consensus-based progression and warrant the initiation of statement). pharmacotherapy (Ungraded consensus-based 3. We suggest collaborative and closely coordinated statement). care of PAH patients involving the expertise of both Remark: Early symptoms concerning for the progression local physicians and those with expertise in PAH care of PAH include new or worsening dyspnea on exertion, (Ungraded consensus-based statement). fatigue, and weakness. As the disease evolves, symptoms Remark: Appropriate care may require the coordinated including lower extremity edema, angina or syncope efforts of cardiologists, pulmonologists, rheumatologists, could signal right heart dysfunction and or failure. Patients with PAH and FC I symptoms should be closely monitored for increased symptoms. Science Center at San Antonio (Dr Levine), San Antonio, TX; A. Cardarelli Hospital (Dr Bossone), Naples, Italy; OhioHealth/The Ohio 5. We suggest that patients at increased risk for the State University (Dr Duvall), Columbus, OH; University of South Alabama (Dr Fagan), Mobile, AL; CHEST (Dr Frantsve-Hawley), development of PAH (Table 1) be monitored for the Glenview, IL; Perelman School of Medicine at the University of development of symptoms of PAH (Ungraded Pennsylvania (Dr Kawut), Philadelphia, PA; University of Utah (Dr Ryan), Salt Lake City, UT; Columbia University Medical Center (Dr consensus-based statement). Rosenzweig), New York, NY; Children’s Hospitals and Clinics of Minnesota (Dr Sederstrom), Minneapolis, MN; Georgetown University 6. We suggest also that contributing causes of PH (eg, Medical Center (Dr Steen), Washington, DC; and University of Col- sleep apnea and systemic hypertension) in patients orado School of Medicine (Dr Badesch), Aurora, CO. with PAH be treated aggressively (Ungraded DISCLAIMER: CHEST Guidelines are intended for general information only, are not medical advice, and do not replace professional medical consensus-based statement). care and physician advice, which should always be sought for any medical condition. The complete disclaimer for this guideline can be accessed at: http://www.chestnet.org/Guidelines-and-Resources. Symptomatic Patients With PAH FUNDING/SUPPORT: This study was funded in total by internal funds Vasoreactivity Testing and Use of Calcium Channel from the American College of Chest Physicians. CORRESPONDENCE TO: David B. Badesch, MD, FCCP, University of Blockers (CCBs) Colorado Denver, 12401 E 17th Ave, Aurora, CO 80045; e-mail: David. 7. We suggest that patients with PAH, in the absence [email protected] of contraindications, should undergo acute Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. vasoreactivity testing using a short-acting agent at a DOI: https://doi.org/10.1016/j.chest.2018.11.030 center with experience in the performance and

566 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] interpretation of vasoreactivity testing (Ungraded with a combination of ambrisentan and tadalafilas consensus-based statement). stated in Recommendation #10. For patients who are unwilling or unable to tolerate combination therapy, Remark: Patients at increased risk of adverse events we advise monotherapy with a currently approved ERA, during acute vasoreactivity testing include those with FC PDE5I inhibitor, or the soluble guanylate cyclase IV symptoms, a low systemic BP, low CO, or PVOD. stimulator riociguat as outlined in the 2014 guidelines. Acute vasoreactivity testing may be complicated by More specifically in these patients: hypotension, and the misinterpretation of results may result in the inappropriate exposure of patients to the 11. We recommend ambrisentan to improve 6MWD risks of a treatment trial with CCBs without the (strong recommendation, low quality evidence). possibility of clinical benefit. Vasoreactivity testing 12-13. We suggest bosentan to delay time to clinical should be performed by individuals with appropriate worsening (Ungraded Consensus-Based Statement). training in test performance and interpretation. 14. We suggest macitentan to delay the time to clinical 8. We suggest that patients with PAH who, in the worsening (Ungraded Consensus-Based Statement). absence of right-sided heart failure or contraindications to CCB therapy, demonstrate acute vasoreactivity 15. We recommend sildenafil to improve 6MWD according to consensus definition, should be considered (strong recommendation, low quality evidence). candidates for a trial of therapy with an oral CCB 16. We suggest tadalafil to improve 6MWD (Ungraded (Ungraded consensus-based statement). Consensus-Based Statement). Remark: Careful follow up of these patients is advised. 17-20. We suggest riociguat to improve 6MWD Long-acting nifedipine or diltiazem, or amlodipine are (Ungraded Consensus-Based Statement), improve suggested. Due to its potential negative inotropic effects, WHO FC (Ungraded Consensus-Based Statement), verapamil should be avoided.1 The daily doses of these delay the time to clinical worsening (Ungraded drugs that have shown efficacy in IPAH are relatively high: Consensus-Based Statement). 120–240 mg for nifedipine, 240–720 mg for diltiazem and up to 20 mg for amlodipine.2 Patients should be followed 21.Wesuggestthatparenteralorinhaled up closely for both safety and efficacy, with an initial prostanoids not be chosen as initial therapy for reassessment after 3 months of therapy. If a patient does treatment naive PAH patients with WHO FC II not improve to functional class I or II, additional or symptoms or as second line agents for PAH patients alternative PAH therapy should be instituted. with WHO FC II symptoms who have not met their treatment goals (Ungraded Consensus-Based Remark: Even though a small percentage (<5%) of PAH Statement). in patients with connective tissue diseases may be vasoreactive, there are no studies to suggest that CCB Patients With WHO FC III Symptoms have been effective. For treatment-naive PAH patients with WHO FC III symptoms who are not candidates for, or who 9. We suggest that CCBs should not be used have failed CCB therapy, we advise that therapy be empirically to treat PAH in the absence of initiated with a combination of ambrisentan and demonstrated acute vasoreactivity (Ungraded tadalafil as stated in Recommendation #10. For consensus-based statement). patients who are unwilling or unable to tolerate PAH-Specific Pharmacotherapies combination therapy, we advise monotherapy with a *10. For treatment naive PAH patients with WHO currently approved ERA, a PDE5I, or the soluble FC II and III, we suggest initial combination guanylate cyclase stimulator riociguat. More fi therapy with ambrisentan and tadalafiltoimprove speci cally in these patients: 6MWD (weak recommendation, moderate quality 22. We recommend the use of bosentan to improve evidence) (Fig 1). 6MWD (strong recommendation, moderate quality evidence). Patients With WHO FC II Symptoms For treatment-naive patients with PAH with WHO FC 23-24. We suggest the use of bosentan to decrease II symptoms who are not candidates for, or who have hospitalizations related to PAH in the short-term failed, CCB therapy, we advise that therapy be initiated (weak recommendation, low quality evidence).

chestjournal.org 567 25. We recommend the use of ambrisentan to 48-49. We suggest IV treprostinil to improve 6MWD improve 6MWD (strong recommendation, low (Ungraded Consensus-Based Statement). quality evidence). 50. In patients with PAH who remain symptomatic on 26-27. We suggest macitentan to improve WHO FC stable and appropriate doses of an ERA or a PDE5I, (Ungraded Consensus-Based Statement) and delay the we suggest the addition of inhaled treprostinil to time to clinical worsening (Ungraded Consensus-Based improve 6MWD (weak recommendation, low quality Statement). evidence). 28-30. We recommend the use of sildenafil to improve 51-52. In patients with PAH who remain symptomatic 6MWD (strong recommendation, low quality evidence), on stable and appropriate doses of an ERA or a to improve WHO FC (Ungraded Consensus-Based PDE5I, we suggest the addition of inhaled iloprost to Statement). improve WHO FC (Ungraded Consensus-Based Statement) and delay the time to clinical worsening 31-34. We suggest the use of tadalafil to improve (Ungraded Consensus-Based Statement). 6MWD (Ungraded Consensus-Based Statement),to improve WHO FC (Ungraded Consensus-Based Patients With WHO FC IV Symptoms Statement), to delay time to clinical worsening For treatment naive PAH patients in WHO FC IV, we (Ungraded Consensus-Based Statement). advise initiation of therapy with a parenteral fi 35-38. We suggest riociguat to improve 6MWD prostanoid agent. More speci cally in these patients: (Ungraded Consensus-Based Statement), improve 53-55. We suggest continuous IV epoprostenol to WHO FC (Ungraded Consensus-Based Statement), improve WHO FC (Ungraded Consensus-Based delay the time to clinical worsening (Ungraded Statement), improve 6MWD (Ungraded Consensus- Consensus-Based Statement). Based Statement). For treatment naive PAH patients with WHO FC III 56. We suggest continuous IV treprostinil to improve symptoms who have evidence of rapid progression of 6MWD (Ungraded Consensus-Based Statement). their disease, or other markers of a poor clinical prognosis, we advise consideration of initial treatment 57-58. We suggest continuous subcutaneous with a parenteral prostanoid. More specifically in treprostinil to improve 6MWD (Ungraded Consensus- these patients: Based Statement). 39-41. We suggest continuous IV epoprostenol to 59. For treatment naive PAH patients in WHO FC IV improve FC (Ungraded Consensus-Based Statement), who are unable or do not desire to manage parenteral improve 6MWD (Ungraded Consensus-Based prostanoid therapy, we advise treatment with an Statement). inhaled prostanoid in combination with an oral PDE5I and an ERA (Ungraded Consensus-Based 42. We suggest continuous IV treprostinil to improve Statement). 6MWD (Ungraded Consensus-Based Statement). Remark: The management of PAH patients with FC IV 43-44. We suggest continuous subcutaneous symptoms who are unable or unwilling to use parenteral treprostinil to improve 6MWD (Ungraded Consensus- prostanoid therapy is particularly challenging because of Based Statement). their high risk of mortality and the lack of data on the efficacy of oral therapies in this group. Very few FC IV For PAH patients in WHO FC III who have evidence patients were included in trials of oral therapies making of progression of their disease, and/or markers of it difficult to determine how they will respond. Further poor clinical prognosis despite treatment with one or studies are needed to determine the efficacy of two classes of oral agents, we advise consideration of combination oral and/or inhaled therapies in patients the addition of a parenteral or inhaled prostanoid. with advanced PAH who are unable or unwilling to More specifically in these patients: tolerate parenteral prostacyclin therapy. Although these 45-47. We suggest IV epoprostenol to improve WHO guidelines have been limited to pharmacologic therapy FC (Ungraded Consensus-Based Statement), improve for PAH, there is consensus among the panel that the 6MWD (Ungraded Consensus-Based Statement). option of lung transplantation should be discussed with

568 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] PAH patients who have advanced disease such 70. For WHO FC III or IV PAH patients with as FC III who fail to improve on medical therapy unacceptable or deteriorating clinical status despite or those in FC IV. Patients who are interested in established PAH-specific therapy with two classes of this option should be evaluated at a transplant PAH pharmacotherapy, we suggest addition of a third center experienced in transplantation for patients class of PAH therapy (Ungraded Consensus-Based with PAH. Statement).

PAH Patients on Established PAH-Specific Therapy Remark: Such patients are ideally evaluated at centers 60. In patients with PAH initiating therapy with IV with expertise in the evaluation and treatment of epoprostenol, we suggest against the routine patients with PAH. simultaneous initiation of bosentan (Ungraded Combination Studies of Endothelin Receptor Consensus-Based Statement). Antagonists and Phosphodiesterase Inhibitors For WHO FC III or IV PAH patients with *71. For stable or symptomatic PAH patients on unacceptable clinical status despite established PAH- background therapy with ambrisentan, we suggest specific monotherapy, we advise addition of a second the addition of tadalafil to improve 6MWD (weak class of PAH therapy to improve exercise capacity. recommendation, low quality evidence) (Fig 1). Such patients are ideally evaluated at centers with expertise in the evaluation and treatment of patients Palliative Care and Supportive Therapies with PAH. More specifically: *72. We suggest incorporating palliative care services 61. In patients with PAH who remain symptomatic on in the management of PAH patients (Ungraded stable doses of an ERA or a PDE5I, we suggest the Consensus-Based Statement) (Fig 2). addition of inhaled iloprost to improve 6MWD *73. We suggest that patients with PAH participate (Ungraded Consensus-Based Statement). in supervised exercise activity as part of the integrated care of their disease 62. In patients with PAH who remain symptomatic (Ungraded on stable doses of an ERA or a PDE5I, we Consensus-Based Statement) (Fig 2). recommend the addition of inhaled treprostinil to Preventive Care improve 6MWD (strong recommendation, low quality evidence). 74. In patients with PAH, we suggest maintaining current immunization against influenza and 63. In patients with PAH who remain symptomatic on pneumococcal pneumonia (Ungraded Consensus- stable doses of established IV epoprostenol, we Based Statement). suggest the addition of sildenafil or up titration of epoprostenol to improve 6MWD (Ungraded Specific Patient Situations Consensus-Based Statement). Pregnancy 64-66. In patients with PAH who remain symptomatic 75. In patients with PAH, we suggest that pregnancy on stable doses of bosentan, ambrisentan or an be avoided (Ungraded Consensus-Based Statement). inhaled prostanoid, we suggest the addition of the 76. When pregnancy does occur in patients with PAH, soluble guanylate cyclase stimulator riociguat to we suggest care at a pulmonary hypertension center improve 6MWD (Ungraded Consensus-Based with experience in this area, using a multidisciplinary Statement), WHO FC (Ungraded Consensus-Based approach including the pulmonary hypertension, the Statement) and to delay the time to clinical worsening high-risk obstetrical, and cardiovascular (Ungraded Consensus-Based Statement). anesthesiology services (Ungraded Consensus-Based 67-69. In patients with PAH who remain symptomatic Statement). on stable doses of a PDE5I or an inhaled prostanoid Altitude and Air Travel we suggest macitentan to improve 6MWD (Ungraded 77. In patients with PAH, we suggest that exposure Consensus-Based Statement), WHO FC (Ungraded to high altitude be avoided, and that supplemental Consensus-Based Statement) and to delay the time to oxygen be used as needed during altitude exposure clinical worsening (Ungraded Consensus-Based or air travel to maintain oxygen saturations > 91% Statement). (Ungraded Consensus-Based Statement).

chestjournal.org 569 Remark: Patients with borderline oxygen saturations at TABLE 1 ] Risk for PAH sea level may require 3-4 L per minute of supplemental 1. Family history of PAH oxygen at high altitude or while traveling on commercial 2. Known genetic mutation for PAH in patient or first aircraft, and those already using supplemental oxygen at degree relative sea level should increase their oxygen flow rate under a. BMPR2 these conditions. b. TBXA2 Surgery c. KNCK3 78. In patients with PAH, we suggest avoiding non- d. EIF2AK4 essential surgery, and when surgery is necessary we e. Caveolin-1 suggest care at a pulmonary hypertension center, 3. Limited cutaneous scleroderma or mixed connective tissue disease using a multidisciplinary approach including the > pulmonary hypertension team, the surgical service, a. FVC/DLCO 1.6 < and cardiovascular anesthesiology with careful b. DLCO 60% monitoring and management of clinical status, c. BNP > 2 times normal oxygenation and hemodynamics postoperatively 4. HIV infection (Ungraded Consensus-Based Statement). 5. Portal hypertension 6. Exposure to drugs or toxins fl Introduction a. Fen uramine/phentermine b. Aminorex World Health Organization (WHO) Group 1 c. Methamphetamine pulmonary arterial hypertension (PAH) (Table 2)3,4 is a d. Dasatinib progressive and fatal disorder for which there was once 7. Congenital heart disease with surgically repaired left to no effective treatment. However, during the past four right shunt within 3-6 mo decades, basic discoveries and pivotal clinical trials have led to the development and regulatory approval of 14 BNP ¼ brain natriuretic peptide; PAH ¼ pulmonary arterial hypertension. medications (Table 3). As a resource for clinicians, the American College of Chest Physicians (CHEST) convened expert panelists In January 2016, the CHEST Guidelines Oversight who developed guidelines for the treatment of PAH. In Committee accepted a proposal to update the 2014 2004, the first guidelines appeared as a supplement to guideline and expert panel report, and they organized a CHEST.5-11 In 2007, a consensus panel updated these broadly constituted guideline and expert panel that guidelines based on evidence published after the 2004 included content experts, methodologists, an ethicist, a guideline and before September 1, 2006.1 In 2014, patient representative, and a pharmacist. The panel CHEST published the most recent guideline and expert followed CHEST’s rigorous process for the development panel report regarding pharmacotherapy for PAH based of the guidelines in line with the National Academy of on evidence available before November 2013.12 Medicine (formerly Institute of Medicine) standards. The panel sought to create a methodologically sound Since November 2013 investigators have published a evidence-based document that is credible, accurate, and substantial body of new evidence related to the useful. treatment of PAH, and two medications received regulatory approval for the treatment of PAH. An orally Several of the new studies reviewed in this update used a active preparation of treprostinil was approved by the composite of clinical end points indicative of PAH Food and Drug Administration (FDA) in December disease progression as the primary outcome. The 2013 and selexipag, an oral prostacyclin receptor definition of clinical failure varied between studies, but agonist, received FDA approval in 2015. Research included events such as death, hospitalization for PAH, groups have provided data on initial treatment with clinical worsening based on a decrease in 6-min walk combinations of PAH-targeted medications and data on distance (6MWD), change in WHO functional class the addition of PAH medications to background (FC), or unsatisfactory long-term response. Although therapy. These new studies and medications have altered these end points were not identical, they represented the therapeutic landscape for patients with PAH and for primary prespecified measures, much like composite the clinicians who care for them. scores for recurrent DVT, DVT extension, new

570 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] TABLE 2 ] Comprehensive Clinical Classification of TABLE 2 ] (Continued) Pulmonary Hypertension 4.2.3 Arteritis 1. PAH 4.2.4 Congenital pulmonary arteries 1.1 Idiopathic PAH 5. Pulmonary hypertension with unclear multifactorial 1.2 Heritable PAH mechanisms 1.2.1 BMPR2 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 5.2 Systemic disorders: sarcoidosis, pulmonary 1.2.3 Unknown histiocytosis, lymphangioleiomyomatosis 1.3 Drug and toxin induced 5.3 Metabolic disorders: glycogen storage disease, 1.4 Associated with: Gaucher disease, thyroid disorders 1.4.1 Connective tissue disease 5.4 Others: tumoral 1.4.2 HIV infection See Table 1 legend for expansion of abbreviation. (Adapted with permis- 1.4.3 Portal hypertension sion from Galie et al3 and Simonneau et al4). 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis pulmonary embolism, or death from pulmonary 1’. Pulmonary veno-occlusive disease and/or pulmonary embolism were used as a primary end point for clinical capillary hemangiomatosis trials of antithrombotic therapies in venous ’ 1 .1 Idiopathic thromboembolism.13,14 The guideline committee 1’.2 Heritable recognized the challenges created by the similar but 1’.2.1 EIF2AK4 mutation different end points reported in more recent PAH trials 1’.2.2 Other mutations and concluded that the small number of studies using 1’.3 Drugs, toxins, and radiation induced composite end points and the differences between the 1’.4 Associated with: end points made it difficult to determine how to weigh 1’.4.1 Connective tissue disease the strength of recommendations. Instead, the guideline 1’.4.2 HIV infection committee chose to use the 6-min walk test as a 1”. Persistent pulmonary hypertension of the newborn clinically relevant outcome, which allowed data to be 2. Pulmonary hypertension because of left heart disease extracted from the Ambrisentan and Tadalafilin 2.1 Left ventricular systolic dysfunction Patients with Pulmonary Arterial Hypertension 2.2 Left ventricular diastolic dysfunction (AMBITION) and Prostacyclin (PGI2) Receptor Agonist 2.3 Valvular disease In Pulmonary Arterial Hypertension (GRIPHON) 2.4 Congenital/acquired left heart inflow/outflow tract (a clinical trial of a prostacyclin receptor agonist as obstruction and monotherapy or add-on therapy in patients with PAH) congenital cardiomyopathies trials. This decision resulted in a weak recommendation 3. Pulmonary hypertension because of lung diseases with moderate quality of evidence for initial and/or hypoxia combination therapy with ambrisentan and tadalafil 3.1 COPD over initial monotherapy with either medication for 3.2 Interstitial lung disease treatment-naïve patients with FC II or III symptoms 3.3 Other pulmonary diseases with mixed restrictive (Recommendation 10) and insufficient evidence to and obstructive pattern make a recommendation for or against the use of 3.4 Sleep-disordered breathing selexipag. However, the committee recognizes that some 3.5 Alveolar hypoventilation disorders clinicians and patients may place a greater value on 3.6 Chronic exposure to high altitude slowing PAH disease progression than on improving 3.7 Developmental lung diseases functional capacity and, if so, may choose to use the 4. Chronic thromboembolic pulmonary hypertension beneficial effect of combination therapy or selexipag 4.1 Chronic thromboembolic pulmonary hypertension on delaying time to clinical worsening as their 4.2 Other pulmonary artery obstructions rationale for using these treatments in the management 4.2.1 Angiosarcoma of PAH. 4.2.2 Other intravascular tumors In summary, this article provides current evidence-based (Continued) guidelines for the treatment of PAH, updating the

chestjournal.org 571 572 umnr reilhpreso;PH hypertension; arterial pulmonary n nuac oeae a ud eiinmkn.CCB decision-making. guide may coverage, bene insurance greater and suggest to data effectiveness 1 Figure

vdneBsdMedicine Evidence-Based Evaluate promptly at PH center – Patients with suspected (Recommendation 2; ungraded udln loih o hraooi hrp o A naut.Weemlil rgotosaepoie,teei ocomparative no is there provided, are options drug multiple Where adults. in PAH for therapy pharmacologic for algorithm Guideline PAH consensus-based)

Upon Confirmation of PAH: • Evaluate severity in a systematic and consistent manner • Coordinate care between local physicians and PH centers • Treat contributing causes of PH aggressively • Incorporate palliative care services in the management of PAH patients ¼ • Participate in supervised exercise activity as part of the integrated care of their disease fi umnr yetnin RV hypertension; pulmonary foeteayoe h te.I hs iutos te atr,sc sptetpeeecs&vle,cost, values, & preferences patient as such factors, other situations, these In other. the over therapy one of t • Maintain current immunization against influenza and pneumococcal pneumonia • Avoid Pregnancy. When pregnancy does occur, we suggest care be provided at a pulmonary hypertension center • Avoid exposure to high altitude. When exposure to high altitude or air travel occurs, use supplemental oxygen as needed to maintain oxygen saturations > 91% • Avoid non-essential surgery. When surgery is necessary we suggest care at a pulmonary ¼

acu hne lce;6MWD blocker; channel calcium hypertension center

(Recommendations 1, 3, 6, 72-78; ungraded consensus-based)

¼ Treat with oral CCB ih etiua;WHO ventricular; right Positive (Recommendation 8; ungraded consensus-based) Suggest acute vasoreactivity testing at a center with experience (Recommendation 7; ungraded consensus-based) Negative, RV Failure or Should not be treated with oral CCB contraindication (Recommendation 9; ungraded

¼ to CCB consensus-based) -i akdsac;FC distance; walk 6-min ¼ ol elhOrganization. Health World [

155#3 Continued monitoring for disease progression Treatment naïve PAH patients (Recommendation 4; ungraded Determine when to start therapy with WHO FC I consensus-based) CHEST Combination therapy with ambrisentan and ¼ Yes tadalafil (Recommendation 10; weak ucinlcas PAH class; functional recommendation, moderate quality evidence)

AC 2019 MARCH Treatment Naïve PAH patients Is the patient willing or able to tolerate with WHO FC II combination therapy? * Monotherapy with either bosentan, No macitentan, ambrisentan, riociguat, sildenafil, or tadalafil (See Box 1) (Continued) ¼ ] iue1 Figure chestjournal.org

Combination therapy with ambrisentan and Yes tadalafil (Recommendation 10; weak – Treatment naïve PAH patients recommendation, moderate quality evidence) Continued with WHO FC III without evidence Is the patient willing and able to tolerate of rapid disease progression combination therapy? or poor prognosis Monotherapy with either bosentan, No macitentan, ambrisentan, riociguat, sildenafil, or tadalafil (See Box 2)

Continuous IV epoprostenol, IV treprostinil, Yes or SC treprostinil (See Box 3) PAH patients with WHO FC III Is the patient willing and able to manage with evidence of rapid disease parenteral prostanoids? progression or poor prognosis No Consider addition of inhaled or oral prostanoid **

Continuous IV epoprostenol, IV treprostinil, Yes or SC treprostinil (See Box 4) PAH patients with Is the patient willing and able to manage WHO FC IV parenteral prostanoids? Inhaled prostanoid in combination with an No oral PDE-5 inhibitor and an oral endothelin receptor antagonist (Recommendation 59; ungraded consensus-based)

For WHO FC III or IV PAH patients with Addition of a second class of PAH therapy unacceptable clinical status despite (See Box 5) established PAH-specific monotherapy Patients with inadequate response to initial therapy For WHO FC III or IV PAH patients with Addition of a third class of PAH therapy unacceptable or deteriorating clinical status (Recommendation 70; ungraded despite established PAH-specific therapy consensus-based) with two classes of PAH pharmacotherapy

Yes List for lung transplantation*** FC III and IV Patients with inadequate response to maximal Is the patient a candidate for lung transplant? pharmacotherapy Incorporate palliative care services in the No management of PAH patients (Recommendation 72; ungraded consensus-based statement) * Combination therapy carries with it costs as well as multiple medications, including the potential for increased adverse events that may be undesirable for some patients. In these situations patients are unwilling or unable to tolerate combination therapy and the panel suggests monotherapy. ** No data available for the use of oral or inhaled prostanoids in patients in whom parental prostanoids are indicated, but patient is unable to comply. Thus, we do not have a specific recommendation for this population *** Lung transplantation is outside the scope of this guideline, which focuses on pharmacotherapy for patients with PAH. Thus, the evidence-based for lung transplants in 573 patients with PAH has not been evaluated by this panel. (Continued) Box 1: Treatment Naïve PAH patients with WHO FC II Box 2: Treatment Naïve PAH patients with WHO FC III

Recommendation Recommendation Drug Outcome Grade Drug Outcome Grade Number Number

strong recommendation, strong recommendation, Ambrisentan Improve 6MWD 11 low quality evidence Improve 6MWD moderate quality 22 evidence Delay time to ungraded consensus- Bosentan Bosentan 12-13 Decrease clinical worsening based statement weak recommendation, hospitalizations related 23-24 low quality evidence to PAH in the short-term Delay time to ungraded consensus- Macitentan 14 clinical worsening based statement strong recommendation, Ambrisentan Improve 6MWD 25 low quality evidence strong recommendation, Sildenafil Improve 6MWD 15 low quality evidence ungraded consensus- Improve WHO FC ungraded consensus- based statement Tadalafil Improve 6MWD 16 based statement Macitentan 26-27 Delay time to clinical ungraded consensus- ungraded consensus- worsening based statement Improve 6MWD based statement strong recommendation, ungraded consensus- Improve 6MWD Improve WHO FC low quality evidence Riociguat based statement 17-20 Sildenafil 28-30 ungraded consensus- Delay time to ungraded consensus- Improve WHO FC clinical worsening based statement based statement

Parenteral or inhaled prostanoids should ungraded consensus- ungraded consensus- Improve 6MWD not be chosen as initial therapy or 21 based statement based as second line agent ungraded consensus- Tadalafil Improve WHO FC 31-34 based statement

Delay time to clinical ungraded consensus- Box 3: PAH patients with worsening based statement WHO FC III with evidence of rapid disease progression or poor prognosis ungraded consensus- Recommendation Improve 6MWD based statement Drug Outcome Grade Number

ungraded consensus- ungraded consensus- Riociguat Improve WHO FC 35-38 Improve WHO FC based statement based statement Continuous IV 39-41 epoprostenol Delay time to clinical ungraded consensus- ungraded consensus- Improve 6MWD worsening based statement based statement

Continuous IV ungraded consensus- Improve 6MWD 42 treprostinil based statement Box 5: Patients with inadequate response to initial therapy

Continuous ungraded consensus- Recommendation subcutaneous Improve 6MWD 43-44 Drug Outcome Grade based statement Number treprostinil In patients with PAH who remain symptomatic on stable doses of an For patients with continued progression of their disease, and/or markers of poor ERA or a PDE5 inhibitor, we suggest the addition of: clinical prognosis despite treatment with one or two classes of oral agents, we advise consideration of the addition of a parenteral or inhaled prostanoid: Inhaled ungraded consensus- Improve 6MWD 61 iloprost based statement ungraded consensus- Improve WHO FC based statement Inhaled strong recommendation, Improve 6MWD 62 IV epoprostenol 45-47 treprostinil low quality evidence ungraded consensus- Improve 6MWD based statement In patients with PAH who remain symptomatic on stable doses of established IV epoprostenol, we suggest one of the following: ungraded consensus- IV treprostinil Improve 6MWD 48-49 based statement Addition of ungraded consensus- sildenafil Improve 6MWD based statement In patients with PAH who remain symptomatic on stable and appropriate doses of 63 an ERA or a PDE5 inhibitor, we suggest the addition of: Up titration of ungraded consensus- Improve 6MWD epoprostenol based statement Inhaled weak recommendation, Improve 6MWD 50 treprostinil low quality evidence In patients with PAH who remain symptomatic on stable doses of bosentan, ambrisentan or an inhaled prostanoid, we suggest the addition of Improve ungraded consensus- WHO FC based statement Inhaled ungraded consensus- 51-52 Improve 6MWD iloprost based statement Delay time to ungraded consensus- ungraded consensus- clinical worsening based statement Riociguat Improve WHO FC 64-66 based statement Delay time to clinical ungraded consensus- worsening based statement

Box 4: PAH patients with WHO FC IV In patients with PAH who remain symptomatic on stable doses of a PDE5 inhibitor or an inhaled prostanoid we suggest Recommendation Drug Outcome Grade Number ungraded consensus- Improve 6MWD based statement ungraded consensus- Improve WHO FC based statement Continuous IV ungraded consensus- 53-55 Macitentan Improve WHO FC 67-69 epoprostenol based statement ungraded consensus- Improve 6MWD based statement Delay time to ungraded consensus- clinical worsening based statement Continuous IV ungraded consensus- Improve 6MWD 56 treprostinil based statement For stable or symptomatic PAH patients on background therapy with ambrisentan

Continuous ungraded consensus- subcutaneous Improve 6MWD 57-58 Addition of Improve ungraded consensus- based statement 71 treprostinil tadalafil 6MWD based statement

Figure 1 – Continued

574 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] Combination therapy with ambrisentan and Yes tadalafil (Recommendation 10; weak recommendation, moderate quality evidence) Treatment Naïve PAH patients Is the patient willing or able to tolerate with WHO FC II combination therapy? * Monotherapy with either bosentan, No macitentan, ambrisentan, riociguat, sildenafil, or tadalafil (See Box 1)

Combination therapy with ambrisentan and Yes tadalafil (Recommendation 10; weak Treatment naïve PAH patients recommendation, moderate quality evidence) with WHO FC III without evidence Is the patient willing and able to tolerate of rapid disease progression combination therapy? or poor prognosis Monotherapy with either bosentan, No macitentan, ambrisentan, riociguat, sildenafil, or tadalafil (See Box 2)

*Combination therapy carries with it costs as well as multiple medications, including the potential for increased adverse events that may be undesirable for some patients. In these situations patients are unwilling or unable to tolerate combination therapy and the panel suggests monotherapy.

Figure 2 – Combination therapy algorithm. Where multiple drug options are provided, there is no comparative effectiveness data to suggest greater benefit of one therapy over the other. In these situations, other factors, such as patient preferences & values, cost, and insurance coverage, may guide decision-making. See Figure 1 for Boxes 1 and 2. See Figure 1 legend for expansion of abbreviations. recommendations that were included in the 2014 statements in areas where there is insufficient evidence. guideline and expert panel report. This document All clinicians and individuals involved in the care and reflects CHEST’s hybrid approach of accommodating management of patients with PAH are the target users of evidence-based recommendations with consensus-based this guideline.

Methods Although CHEST’s COI protocol clearly limits involvement of guidelines panel members who have potential industry and academic Expert Panel Composition conflicts,15 the unique circumstances dictated by research in this rare fi The quali cations of the suggested cochairs of the guideline were reviewed disease presented the option of preparing a document without the ’ and approved by CHEST s Professional Standards Committee. Panelists expertise of hands-on subject matter experts or involving those with were nominated by the cochairs based on their expertise relative to the experience and knowledge who also have shared—and gained—their scope of the guideline. The complete guideline panel consisted of three expertise with industry research programs in the effort to improve cochairs (D. J. L., D. B. B., and J. R. K.), three panelists (G. E., S. M. K., care for this patient population. As with all CHEST programs, the and N. S.), and panel representatives from the following organizations: principals’ COI disclosures are published and available to all readers. Pulmonary Hypertension Association (L. D. and E. B. R.), American In an attempt to provide clinicians worldwide with the best evidence Thoracic Society (K. F.), American Heart Association (J. J. R.), a analyzed by subject matter experts via its rigid methodologic process, ’ representative from CHEST s Guideline Oversight Committee (E. B.), CHEST has chosen to rely on the expertise of panel members who, and a patient representative (S. R.). although having disclosed potential conflicts, are among the small but growing number of experts in this field. Conflicts of Interest Key Question Development All panel nominees were reviewed for their potential conflicts of interest (COIs) by CHEST’s Professional Standards Committee. Key clinical questions were developed using the population, Nominees who were found to have no substantial COIs were intervention, comparator, outcome (PICO) format. This guideline is “ approved, whereas nominees with either potential intellectual or an update of the 2014 CHEST guideline, Pharmacologic Therapy financial COIs that were manageable were approved with for Pulmonary Arterial Hypertension in Adults: CHEST Guideline ”12 management. Panelists who were approved with management were and Expert Panel Report. That guideline used the Agency for prohibited from drafting and voting on recommendations in which Healthcare Research and Quality (AHRQ) Comparative Effectiveness “ they had substantial potential COIs. Additionally, in situations where Report, Pulmonary Arterial Hypertension: Screening, Management, ”16 fi one of the cochairs had a conflict preventing engagement based on and Treatment, for the evidence review. The guideline speci cally “ the management terms, an unconflicted cochair led the panel focused on key question 3 of that report, which states, For patients discussion. with PAH, what are the comparative effectiveness and safety of monotherapy or combination therapy for PAH using calcium As with many rare diseases, PAH has historically lacked research funding channel blockers, prostanoids, endothelin antagonists or from governmental agencies because of the relatively few numbers of phosphodiesterase inhibitors on intermediate term and long-term patients who would benefit. Patient advocacy organizations’ fundraising patient outcomes?” Because this current guideline is an update, the and public awareness campaigns have until recently provided the bulk of PICO format was developed based on this key question and used the resources for scientific research related to etiology, diagnosis, and AHRQ methods for defining inclusion and exclusion criteria. The treatment of patients with PAH. Similarly, the number of basic science AHRQ methodology did not use composite end points because of researchers and clinicians involved in the field has been low, yielding a the lack of comparability in definition among studies and the small number of subject matter experts who have been able to conduct assignment of equal importance to events included in the composites clinical trials that have resulted in 14 targeted therapies available within such as mortality, hospitalization, transplant, and changes in the past 25 years. 6MWD.16 The panel agreed with this decision and chose to maintain

chestjournal.org 575 TABLE 3 ] Currently Approved Medications for Treatment of Pulmonary Arterial Hypertension

Class Drug Route of Administration Dose Prostacyclin Epoprostenola IV infusion 2 ng/kg/min derivatives Increase as tolerated Iloprost Inhaled 2.5 or 5.0 mg 6-9 inhalations/d Treprostinil Oral 0.25 mg bid or 0.125 mg tid Increase 0.125 mg bid every 3-4 d Inhaled 18–54 mg (3-9 inhalations) 4 times daily Subcutaneous 1.25 ng/kg/min; increase 1.25 ng/kg/min per or IV infusion week based on clinical response; after week 4 increase by 2.5 ng/kg/min per week based on clinical response Endothelin receptor Bosentan Oral 125 mg twice daily antagonists Ambrisentan Oral 5 or 10 mg once daily Macitentan Oral 10 mg once daily Phosphodiesterase Sildenafil Oral 20 mg every 8 h type-5 inhibitors IV injection Tadalafil Oral 40 mg once daily Soluble cGMP Riociguat Oral 0.5-1.0 mg every 8 h (increase 0.5 mg every stimulators 2 wk as tolerated to maximum dose 2.5 mg) Prostacyclin receptor Selexipag Oral 200 mg twice daily agonists Increase as tolerated to maximum dose of 16,000 mg twice daily aAvailable in a pH neutral (Flolan) or highly alkaline (Veletri) diluent. The latter provides increased drug stability at room temperature.

the exclusion of composite end points for these reasons and also to Systematic Literature Search maintain consistency between the original and updated review. A systematic literature search for individual studies for this PICO was Among study outcomes, the 6MWD was one of the most frequently conducted using the following databases: MEDLINE via PubMed and reported in studies. The AHRQ evidence review recognized that not the Cochrane Library. Searches for phase I were updated from January all change in 6MWD was clinically important. They used the 2012 to July 2016. The search strategy from the AHRQ review was used fi minimally important difference (MID) speci ed in PAH literature as with slight modification to focus on Group 1 PAH (e-Table 1). All fi fi 16 33 m to de ne clinically signi cant improvement. We maintained searches were also limited to English language. Searches for phase II fi this de nition for the review. modified the phase I search to retrieve the additional interventions (e-Table 1). During discussion and development of the PICO, the panel decided it was important to update the pharmacologic therapies by adding orally The panelists reviewed the titles and abstracts of the search results active prostacyclins and prostacyclin receptor agonists and to add independently and in parallel to identify potentially relevant articles fi nonpharmacologic interventions. Therefore, the nal PICO question based on the inclusion and exclusion criteria (Table 4). All addressed in this guideline is as follows: discrepancies were resolved by discussion. Studies deemed eligible then underwent a second round of full-text screening by the same For adult patients with PAH, what are the comparative effectiveness pair of panelists for final inclusion. Again, discrepancies were and safety of (1) mono- or combination pharmacotherapies using resolved by discussion. Important data from each included study calcium channel blockers, prostanoids, endothelin antagonists, were then extracted into structured evidence tables completed phosphodiesterase inhibitors, soluble guanylate cyclase independently and in parallel by two abstractors. stimulators, or orally active prostacyclin derivatives and prostacyclin receptor agonists; (2) cardiopulmonary rehabilitation; (3) palliative care; (4) supportive care; and (5) preventive care on Quality Assessment intermediate-term and long-term patient outcomes? (Table 4). Included studies were assessed for quality and risk of bias using the following assessment tools: To maintain the integrity of the update process and to add the additional interventions, we decided to manage the evidence review search and Documentation and Appraisal Review Tool for systematic selection of eligible studies in two phases. Phase I was an update of review13 the prior review that was conducted by AHRQ, and phase II was a Cochrane risk of bias tool for randomized controlled trials14 review of the new pharmacologic and nonpharmacologic interventions. Risk of bias tool for observational intervention studies17

576 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] TABLE 4 ] Population, Intervention, Comparator, Outcome Question

Exclusion Study Characteristic Inclusion Criteria Criteria For adult patients with pulmonary arterial hypertension, what are the comparative effectiveness and safety of (1) mono- or combination pharmacotherapies using calcium channel blockers, prostanoids, endothelin antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, or selexipag; (2) cardiopulmonary rehabilitation; (3) palliative care; (4) supportive care; and (5) preventive care on intermediate- and long-term patient outcomes? Population Adult patients with pulmonary arterial hypertension: Group 1 within the Children pulmonary hypertension World Health Organization clinical classification Interventions Calcium channel blockers (amlodipine, diltiazem, nifedipine) Prostacyclin derivatives or related (epoprostenol, treprostinil, iloprost) Endothelin antagonists (bosentan, ambrisentan, macitentan) Phosphodiesterase inhibitors (sildenafil, tadalafil) Soluble guanylate cyclase stimulator (riociguat) Selexipag Cardiopulmonary rehabilitation Palliative care Supportive care (supplemental oxygen, diuretics, digoxin, anticoagu- lants, physical therapy/rehabilitation) Preventive care (influenza and pneumonia immunizations, contracep- tion, high-risk pregnancy management, avoiding nonessential surgery and perioperative risk management) Comparators One pharmacotherapy vs another pharmacotherapy as monotherapy Monotherapy vs combination therapy, including either as add-on therapy or as an initial treatment regimen using combination therapy One combination therapy to another combination therapy Cardiopulmonary rehabilitation vs pharmacotherapy Cardiopulmonary rehabilitation plus pharmacotherapy vs pharmacotherapy alone Palliative care vs no palliative care Outcomes Intermediate-term outcomes (hemodynamic parameters, dyspnea, Composite end points 6-min walk distance considering MID) Long-term outcomes (functional class, QoL, right-sided heart failure or right ventricular dysfunction, mortality, PAH-related hospitalization, need for interventional procedures) Study design Systematic reviews (with or without, meta-analyses), RCTs, prospective and retrospective cohort studies

MID ¼ minimally important difference; QoL, quality of life; RCT ¼ randomized controlled trial. See Table 1 legend for expansion of other abbreviation.

Grading the Evidence and Development of The 2014 guideline included multiple ungraded statements referencing Recommendations use of interventions to improve cardiopulmonary hemodynamic Grading of Recommendations, Assessment, Development and parameters that were not supported by evidence addressing overall Evaluation (GRADE) evidence profiles were created to grade the patterns of hemodynamic changes. The rationale used at that time was overall quality of the body of evidence supporting the outcomes for that because only evidence on single parameters (eg, for pulmonary each intervention based on five domains: risk of bias, inconsistency, vascular resistance [mean pulmonary artery pressure], cardiac output, indirectness, imprecision, and publication bias. The quality of the cardiac index, right atrial pressure) was available in some evidence for each outcome is rated as high, moderate, low, or very circumstances, ungraded statements were included to alert clinicians to low according to GRADE standards.18,19 when improvements in individual parameters were found. However, because neither GRADE methodology nor the CHEST approach toward The panel drafted recommendations for each key clinical question that consensus statements support ungraded statements in the absence of had sufficient evidence. Recommendations were graded using the evidence, all references to potentially improved cardiopulmonary CHEST grading system (Table 5), based on GRADE, which is hemodynamic outcomes were removed from this updated guideline composed of two parts: the strength of the recommendation (either when there was a lack of evidence to support such statements. strong or weak) and a rating of the overall quality of the body of evidence.20 In instances where there was insufficient evidence, but a recommendation was still warranted, a weak suggestion was Consensus Development developed and “Ungraded Consensus-Based Statement” replaced the All drafted recommendations and suggestions were presented to the grade. The 2014 guideline used CHEST’s previous grading system, panel in an anonymous voting survey to achieve consensus through modified GRADE. All unchanged recommendations and suggestions a modified Delphi technique. Panelists were requested to indicate from that iteration of the guideline have been converted to standard their level of agreement on each statement, using a 5-point Likert GRADE format for consistency with current methodology.21 scale derived from the GRADE grid.20,22 Panelists also had the

chestjournal.org 577 TABLE 5 ] CHEST Grading System

Grade of Benefit vs Risk and Methodologic Strength of Recommendation Burdens Supporting Evidence Implications Strong Benefits clearly We are very confident that Recommendation can apply to most recommendation, outweigh risk and the true effect lies close to patients in most circumstances. high-quality burdens, or vice that of the estimate of the Further research is very unlikely to evidence versa. effect. change our confidence in the estimate of effect. Strong Benefits clearly We are moderately confident Recommendation can apply to most recommendation, outweigh risk and in the effect estimate: the patients in most circumstances. moderate-quality burdens, or vice true effect is likely to be Higher-quality research may well evidence versa. close to the estimate of the have an important impact on our effect, but there is a confidence in the estimate of effect possibility that it is and may change the estimate. substantially different. Strong Benefits clearly Our confidence in the effect Recommendation can apply to most recommendation, outweigh risk and estimate is limited: the patients in many circumstances. low-quality burdens, or vice true effect may be Higher-quality research is likely to evidence versa. substantially different from have an important impact on our the estimate of the effect. confidence in the estimate of effect and may well change the estimate. Strong Benefits clearly We have very little Recommendation can apply to most recommendation, outweigh risk and confidence in the effect patients in many circumstances. very low-quality burdens, or vice estimate: the true effect is Higher-quality research is likely to evidence versa. likely to be substantially have an important impact on our different from the estimate confidence in the estimate of effect of effect and may well change the estimate. Weak (conditional) Benefits closely We are very confident that The best action may differ depending recommendation, balanced with risks the true effect lies close to on circumstances or patients’ or high-quality and burden. that of the estimate of the societal values. Further research is evidence effect. very unlikely to change our confidence in the estimate of effect. Weak (conditional) Benefits closely We are moderately confident Best action may differ depending on recommendation, balanced with risks in the effect estimate: the circumstances or patients’ or moderate-quality and burden. true effect is likely to be societal values. Higher-quality evidence close to the estimate of the research may well have an effect, but there is a important impact on our confidence possibility that it is in the estimate of effect and may substantially different change the estimate. Weak (conditional) Uncertainty in the Our confidence in the effect Other alternatives may be equally recommendation, estimates of estimate is limited: the reasonable. Higher-quality research low-quality benefits, risks, and true effect may be is likely to have an important impact evidence burden; benefits, substantially different from on our confidence in the estimate of risk, and burden the estimate of the effect. effect and may well change the may be closely estimate. balanced. Weak (conditional) Uncertainty in the We have very little Other alternatives may be equally recommendation, estimates of confidence in the effect reasonable. Higher-quality research very-low quality benefits, risks, and estimate: the true effect is is likely to have an important impact evidence burden; benefits, likely to be substantially on our confidence in the estimate of risk, and burden different from the estimate effect and may well change the may be closely of effect. estimate. balanced. Ungraded consensus-based suggestions Ungraded Uncertainty because Insufficient evidence for a Future research may well have an Consensus-Based of lack of evidence graded recommendation. important impact on our confidence Statement but expert opinion in the estimate of effect and may that benefits change the estimate. outweigh risk and burdens or vice versa.

578 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] option to provide open-ended feedback on each statement with 80% consensus agreement to be accepted. Panelists with COIs suggested edits or general comments. According to CHEST policy, related to the individual statements were not allowed to vote (per each statement required a 75% voting participation rate and at least the terms of their COI management).

Results intermediate, or high risk of 1-year mortality,2 and The flowchart in e-Figure 1 presents the results of the predictive equations for survival in PAH have been systematic search for phase I. The updated search developed (Registry to Evaluate Early And Long-term identified 300 potentially new studies. Of those, 106 Pulmonary Arterial Hypertension Disease Management were selected for full-text review, and of those only four [REVEAL], French Pulmonary Hypertension Network studies met all inclusion criteria.23-26 Those four studies predictive equation).40,41 However, none of these tools each examined different combination therapies. Three of have been prospectively validated, and the ability of any the studies earned a low risk of bias rating23-25; the of these tools to identify which patients are more likely fourth earned an unclear rating.26 to derive benefit from a particular therapy has not been formally studied. Lacking data from such studies, we The flowchart in e-Figure 2 presents the results of the provide recommendations that are based on the WHO systematic search for phase II. The search for new FC of the patients enrolled in the clinical studies we interventions identified 379 citations. Of those, 30 were evaluated. Please refer to the full treatment algorithm in selected for full-text review, and of those, only 12 studies Figure 3. met all inclusion criteria.27-38 Of these, two studies evaluated selexipag.27,28 One systematic review, which Because of the rare occurrence of PAH in the general included two of the primary studies we identified, population, most physicians, including those whose evaluated exercise-based rehabilitation.29 One study subspecialty practice includes pulmonary and evaluated inspiratory muscle training.30 One systematic cardiology, are unlikely to encounter sufficient numbers review and three primary studies evaluated of patients with PAH to gain meaningful experience anticoagulation.31-34 One study evaluated antiplatelet with the diagnosis and management of this disease. For therapy,36 and one evaluated selective serotonin this reason, we suggest that newly diagnosed patients reuptake inhibitors (SSRIs).35 Both systematic reviews with PAH be referred to a center with experience in were well designed and executed and earned a good managing PAH, ideally before treatment is initiated. quality rating; however, they found little or no evidence Until recently, there was no formal process for relevant to our question. All of the 10 primary studies identifying centers that had expertise in managing PAH. earned an unclear risk of bias rating. In 2015, the Pulmonary Hypertension Association began the PH Care Centers initiative. This program accredits Centers of Comprehensive Care and Regional Clinical Pharmacologic Therapy for PAH in Adults Programs in the United States based on their willingness Lacking head-to-head comparisons of pharmacologic to participate in the program and their ability to agents for the treatment of PAH, and because of their demonstrate proficiency in managing patients with different desirable and undesirable effects for patients, PAH. Currently, there are > 50 Pulmonary we recommend that drug therapy be chosen based on a Hypertension Association (PHA)-accredited centers methodic evaluation of disease severity, the risk for throughout the United States. Many other centers further short-term deterioration, and the preferences outside of the PHA accreditation program also have and values of the patient. The optimal method of extensive management experience in PAH. Although evaluation has not been studied. Previous guidelines differences in outcome between patients managed with have suggested that WHO FC, echocardiographic or without the advice of an expert center have not been assessment of right ventricular function, 6MWD, plasma formally studied, referral to such centers is brain natriuretic peptide or N-terminal pro-brain recommended by treatment guidelines from the Joint natriuretic peptide level, hemodynamic measurements, Task Force for the Diagnosis and Treatment of and cardiopulmonary exercise testing in addition to Pulmonary Hypertension of the European Society of patient symptoms and clinical findings can be useful Cardiology and the European Respiratory Society2 and indicators of disease severity and response to by the World Symposium on Pulmonary Hypertension. treatment.39 Specific parameters for each of these Considering the increased availability of centers that variables have been proposed to identify patients at low, specialize in the management of PAH, the guideline

chestjournal.org 579 Evaluate promptly at PH center Patients with suspected (Recommendation 2; ungraded PAH consensus-based)

Upon Confirmation of PAH: • Evaluate severity in a systematic and consistent manner • Coordinate care between local physicians and PH centers • Treat contributing causes of PH aggressively • Incorporate palliative care services in the management of PAH patients • Participate in supervised exercise activity as part of the integrated care of their disease • Maintain current immunization against influenza and pneumococcal pneumonia • Avoid Pregnancy. When pregnancy does occur, we suggest care be provided at a pulmonary hypertension center • Avoid exposure to high altitude. When exposure to high altitude or air travel occurs, use supplemental oxygen as needed to maintain oxygen saturations > 91% • Avoid non-essential surgery. When surgery is necessary we suggest care at a pulmonary hypertension center

(Recommendations 1, 3, 6, 72-78; ungraded consensus-based)

Treat with oral CCB Positive (Recommendation 8; ungraded consensus-based) Suggest acute vasoreactivity testing at a center with experience (Recommendation 7 ; ungraded consensus-based) Negative, RV Failure or Should not be treated with oral CCB contra-indication (Recommendation 9 ; ungraded to CCB consensus-based)

Figure 3 – General measures algorithm. committee agreed that patients should be offered access pro-brain natriuretic peptide levels provide an to these resources whenever feasible. assessment of cardiac impairment that may be useful in guiding therapy. A combination of variables, each Despite variability in clinicians’ approaches, the WHO evaluated in a consistent manner, is recommended. All FC (Table 6)42 provides a symptom-based means of treatment decisions should be informed by patient assessing disease impact on a patient’s life.43 Similarly, preferences and values, goals, and assessments of health- despite limitations in its use as a surrogate measure, the related quality of life. 6MWD provides functional information. Additionally, hemodynamic measurements, echocardiographic Additionally, the panel acknowledges that the drugs assessment, and brain natriuretic peptide or N-terminal reviewed in this guideline are expensive and that current costs should be taken into account with other information on efficacy, safety, and the patient’s TABLE 6 ] World Health Organization Functional individual situation when selecting the most Classification of Patients With PH appropriate therapy. Furthermore, multiple drug Classification options are provided for many of the patient Class I: patients with PH but without resulting limitation conditions. In these circumstances, no comparative of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near effectiveness data are available to suggest greater syncope. benefit of one therapy over the other. In these Class II: patients with PH resulting in slight limitation of situations, other factors, such as patient preferences physical activity. They are comfortable at rest. and values, cost, and insurance coverage, may guide Ordinary physical activity causes undue dyspnea or decision-making. fatigue, chest pain, or near syncope.

Class III: patients with PH resulting in marked limitation Newly Approved Therapies of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, Selexipag: In the first FDA phase 2 trial, 43 adult chest pain, or near syncope. patients with symptomatic PAH (receiving stable Class IV: patients with PH with inability to carry out any endothelin receptor antagonist [ERA] and/or physical activity without symptoms. These patients manifest signs of right-sided heart failure. Dyspnea phosphodiesterase type-5 inhibitor [PDE5I] therapy) 27 and/or fatigue may even be present at rest. Discomfort were randomized to receive either selexipag or placebo. is increased by any physical activity Dosage was up-titrated in 200-mg increments from

PH ¼ pulmonary hypertension. (Adapted with permission from Rubin et 200 mg twice daily on day 1 to the maximum tolerated al.42) dose by day 35 (maximum allowed dose of 800 mg twice

580 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] daily). Mean change in 6MWD from baseline to Combination Trials in PAH Since 2014 17 weeks was reported as an increase of 24.2 m Since the 2014 guidelines were published, four studies (95% CI, 23.7 to 72.2 m) for the selexipag group, with have been completed in which PAH-specific therapies no change in 6MWD reported for the placebo group. In have been used in combination, resulting in some this study, the mean difference between the treatment changes and additions to the previous and control groups, and CIs, were not reported. This recommendations.23-26 study was limited by its small size and is described as a Combination Studies of ERAs and Phosphodiesterase “proof of concept” study. Inhibitors: Since the 2014 guidelines, three studies have Selexipag was then studied in an FDA phase 3 trial in been published using combinations of ERAs and PDE5Is which 1,156 patients with PAH were randomly assigned in different scenarios. to receive placebo or selexipag in individualized doses Bosentan Added to Sildenafil Therapy in Patients m 28 (maximum dose, 1,600 g twice daily). The primary With PAH: McLaughlin et al24 conducted a multicenter end point was a composite of death from any cause or a prospective, double-blind, event-driven trial of patients complication related to PAH up to the end of the with symptomatic PAH who were on stable therapy with fi treatment period (de ned for each patient as 7 days after sildenafilat$ 20 mg three times daily for at least the date of the last intake of selexipag or placebo). There 3 months. Three hundred and thirty-four patients were fi was no signi cant difference in PAH mortality (hazard randomized to receive placebo or bosentan at 62.5 mg ¼ ratio [HR], 0.86; 95% CI, 0.63-1.18; P .18), death from twice daily for 1 month followed by 125 mg twice daily. ¼ any cause (HR, 0.97; 95% CI, 0.74-1.28; P .42), or The between-group mean difference for 6MWD was absence of worsening in WHO FC (OR, 1.16; 99% CI, found to be 21.8 m (95% CI, 5.9-37.8; P ¼ .0106) in the ¼ 0.81-1.66; P .28) between the two study groups. bosentan-treated patients compared with placebo. Although the change in 6MWD within the selexipag Although this increase was found to be statistically fi group was statistically signi cant (12 m; 99% CI, 1-24), significant, it was less than the MID (33 m) identified in fi fi it did not meet our prespeci ed MID de ned in the PAH the methodology section of this guideline. No fi literature as 33 m for clinically signi cant improvement. differences between the two groups were identified in Because of the use of a composite score as a primary end other outcomes of interest (change in WHO FC or time point and the lack of a clinically relevant change in to death from any cause). There is currently insufficient 6MWD, the committee concluded that there is evidence to make a recommendation for or against the fi insuf cient evidence at this time to make a addition of bosentan to patients on sildenafil. recommendation for or against the use of selexipag. Initial Use of Ambrisentan Plus TadalafilinPAH:In Oral Treprostinil: Oral treprostinil is FDA-approved as the Ambrisentan and Tadalafil in Patients with monotherapy for PAH. Our updated search identified Pulmonary Arterial Hypertension (AMBITION) trial, one randomized controlled trial on monotherapy by Jing Galie et al23 studied combination therapy with et al44 (FREEDOM-M), which assessed the efficacy and ambrisentan (10 mg daily) plus tadalafil (40 mg daily) safety of monotherapy with oral treprostinil compared vs either ambrisentan or tadalafil alone in PAH. with placebo. Investigators found that among patients A total of 610 patients were randomized 2:1:1 to receive receiving oral treprostinil, 6MWD significantly ambrisentan (10 mg daily) plus tadalafil (40 mg daily) improved at 8 weeks (17 m; 95% CI, 1-33 m; P ¼ .0307) vs ambrisentan plus placebo vs tadalafil plus placebo, and 12 weeks (23 m; 95% CI, 4-41 m; P ¼ .0125). This respectively. The primary outcome was the time to first study was ultimately excluded from our review because event of clinical failure defined as the composite end point of the inclusion of pediatric patients ($ 12 years of age); for death, hospitalization for worsening PAH (including therefore, the panel was unable to make a transplant, atrial septostomy, and initiation of parenteral recommendation for or against the use of oral prostanoid therapy), disease progression (defined as a treprostinil as monotherapy. 15% decrease in the 6MWD combined with a FC III or IV There is also currently no evidence to support its at two consecutive visits separated by 14 days), or use in add-on or combination therapeutic unsatisfactory long-term clinical response in patients approaches, as subsequently discussed in the completing at least 6 months of the trial (assessed as a Combination of Prostacyclin Therapy with ERAs and decrease in 6MWD from baseline and FC III symptoms at PDE5Is section. two visits separated by at least 6 months).

chestjournal.org 581 The median change from baseline for 6MWD improved treatment options based on each individual situation more in the combination treatment group than the and what is in the best interest for the particular patient. pooled monotherapy groups (49 vs 24 m, respectively; Recommendation: *71. For stable or symptomatic < P .001) (e-Table 2). There was no effect on the WHO PAH patients on background therapy with FC. The improvement in 6MWD in the treatment group ambrisentan, we suggest the addition of tadalafilto suggests that initial combination treatment may be more improve 6MWD (weak recommendation, low quality fi ef cacious than monotherapy in improving exercise evidence). capacity. Because there was only one study, and the clinical outcome measured demonstrated a borderline Combination of Prostacyclin Therapy With ERAs and clinically significant effect on 6MWD, the panel PDE5Is: Since publication of the 2014 guidelines, oral supported a weak suggestion instead of a strong treprostinil was approved for treatment of PAH. Two recommendation. It is important that each physician studies examined the effect of the addition of oral and patient work together to decide best treatment treprostinil to background ERAs and/or PDE5Is.25 options based on each individual situation and what is in Tapson et al25 performed an international multicenter, the best interest for the particular patient. double-blind, placebo controlled trial of the addition of Recommendation: *10. For treatment naive PAH oral treprostinil to patients with PAH receiving patients with WHO FC II and III, we suggest initial background therapy with ERAs and/or PDE5Is in the combination therapy with ambrisentan and tadalafil FREEDOM-C2 trial. No significant difference was to improve 6MWD (weak recommendation, moderate shown in the primary outcome of improvement in the quality evidence). 6MWD from baseline to 16 weeks (median difference, 10 m; 95% CI, 2to22m;P ¼ .089). Randomized Study of Adding Tadalafil to Existing 26 This study is limited by a high percentage of premature Ambrisentan in PAH: Zhuang et al conducted a discontinuations, relatively short treatment duration, prospective, double-blinded, randomized controlled relatively small size, and potential ceiling effect of the study to investigate the efficacy of the addition of oral 6MWD in patients already receiving multiple tadalafil in patients receiving background ambrisentan background therapies. therapy for PAH. One hundred and twenty-four patients with symptomatic idiopathic pulmonary At this time, there is insufficient evidence to make a arterial hypertension (IPAH), heritable PAH, or PAH recommendation for or against the addition of bid oral associated with connective tissue disease; anorexigen treprostinil to patients on background therapy with use; or repaired congenital heart disease who were ERAs and/or PDE5Is. treated with ambrisentan (10 mg daily) for $ Additional Considerations for Combination 4 months received either placebo or tadalafil(40mg Therapies in PAH: As discussed in the 2014 guidelines daily) for 16 weeks. and previously reviewed, the addition of therapies to At 16 weeks, there was a nonsignificant improvement in existing treatments or the use of multiple therapies as 6MWD from baseline in the placebo group (mean initial treatment remains a complicated issue. change, 18.3 m; 95% CI, 4.3-34.8; P ¼ not significant) Consideration of the addition of new therapies to a and a significant improvement in the tadalafil group patient already on PAH treatment requires that the (mean change, 54.4 m; 95% CI, 30.2-80.1; P < .05) clinician assess whether the patient has received an (e-Table 3). Compared with the placebo group, the adequate trial of the initial therapy to assess efficacy and increase in the treatment group was found to be clinical status. This assessment includes evaluation of significant (P ¼ .042), but the mean difference between the duration of therapy, the expected response to the the treatment group and control group, and CIs, were therapy, the observed response to the therapy, and the not reported. Change in WHO FC did not differ patient’s severity of illness and pace of decline. between groups at 16 weeks. Because there was only one Unacceptable clinical status will vary for individual study, and the clinical outcome measured demonstrated patients and clinicians, but symptomatic limitation of a borderline clinically significant effect on 6MWD, the desired physical activities usually guides these decisions. panel supported a weak suggestion instead of a strong The clinician must then review the evidence available to recommendation. It is still important that each determine which additional therapy is likely to benefit physician and patient work together to decide best the patient the most while limiting expected adverse

582 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] events. The studies reviewed here represent the management of disease burden, pain, and symptoms of increasing interest in assessing combination therapy in chronic or acute needs. The addition of palliative care additive or initial strategies and provide some interventions to assist in management of disease burden framework to aid the clinician in these decisions. and symptoms can often be beneficial to improving patient quality of life. As identified in the 2014 guidelines, studies adding a second PAH-specific drug to already initiated PAH- Recommendation: *72. We suggest incorporating specific therapy have routinely continued the initial palliative care services in the management of PAH drug. None of the studies reviewed here indicate that the patients (Ungraded Consensus-Based Statement). patient has or has not had a therapeutic benefit of the initial treatment but instead state the patients are stable. Pulmonary Rehabilitation: Pulmonary rehabilitation fi Published reports have not indicated whether clinical has been shown to be safe and bene cial in improving benefit had been noted in response to the initial agent. exercise capacity and quality of life in chronic lung fi 46-48 Indeed, many authors cite the potential ceiling effect of disease (ie, COPD, lung cancer, pulmonary brosis). background treatments on outcome measures as Studies exist on many aspects related to supervised limitations to identifying a benefit of their intervention, exercise-based rehabilitation in pulmonary hypertension 49-52 but fail to provide enough clinical information to make (PH). International guidelines recommend that determination. We continue to lack data to inform integrating exercise training into the care of patients 2 whether such practice is appropriate or whether it would with PAH. Pulmonary rehabilitation, however, was be more appropriate to discontinue an initial agent if not evaluated as a therapy for PAH in the 2014 clinical benefit had not been observed after its initiation, CHEST guidelines. For this iteration of the CHEST fi as was done in a recently published open-label study for guidelines, no studies were identi ed in our review riociguat.45 A lack of clinical improvement or a that directly addressed pulmonary rehabilitation in worsening of clinical status with therapy might represent adults with PAH. fi an absence of bene t or even harm from the treatment, Exercise Training: Our search identified three studies progression of disease, or a combination of these factors. that assessed exercise training in PH.29,37,38 The studies Because all drugs have potential adverse effects, and by Ehlken et al38 and Weinstein et al37 were included in fi PAH-speci c therapies are costly, this remains an a full systematic review by Morris et al.29 To avoid important gap in the evidence available from clinical double counting, we used the systematic review only. trials and a problematic issue for clinical care. More Although the systematic review included other studies combination studies may inform clinicians to potential on PH, only two small studies (totaling 36 patients additive or even synergistic effects in the future. combined) were specific to patients with Group 1 PAH and were of low quality (e-Table 4). Palliative Care and Supportive Therapies Six studies were identified for palliative care and Profile Inspiratory Muscle Training: One small study 30 supportive therapies. After full-text review, no eligible by Saglam et al met our inclusion criteria. Twenty-nine studies on palliative care and PAH exist to provide direct clinically stable patients with PAH were randomly recommendations. The studies relating to supportive assigned to inspiratory muscle training program or to a care measures included four on anticoagulation,31-34 one sham protocol. After 6 weeks, a significant change in on antiplatelet therapy,36 and one on SSRI additions.35 6MWD was seen in the inspiratory muscle training group (426.93 97.76 before and 476.43 90.11 after; Palliative Care: Palliative medicine is a well-established P ¼ .001), and no significant change was seen in the and growing field with clearly documented benefits to control group (357.24 137.17 before and 334.00 patients and outcomes. Other lung diseases such as lung 121.60 after; P ¼ .109) (e-Table 5). The difference cancer have shown significant improvements in between groups was found to be significant (P < .001), outcome measurements with the addition of palliative but it is unclear if this difference is because of group care to standard interventions. Our search identified no differences at the start of the study. eligible studies to directly evaluate the effectiveness of palliative care therapies in conjunction with standard Recommendation: *73. We suggest that patients with interventions for PAH, but this lack of evidence in the PAH participate in supervised exercise activity as literature does not negate the potential benefits palliative part of the integrated care of their disease (Ungraded care offers to all patients and families for assisting in Consensus-Based Statement).

chestjournal.org 583 Anticoagulation: Four studies were identified in our TABLE 7 ] International Society for Heart and Lung review addressing anticoagulation.31-34 The Ezedunukwe Transplantation Recommendations: Referral for Transplantation for PAH et al systematic review31 evaluated randomized controlled trials that addressed the effectiveness and WHO FC III (with worsening symptoms despite optimal therapy) potential adverse events of anticoagulation in the WHO FC IV symptoms management of PH. No eligible studies were identified Rapidly progressive disease in this review. Olsson et al32 conducted a retrospective cohort analysis from the Comparative, Prospective Use of parenteral PAH therapy regardless of symptoms or FC Registry of Newly Initiated Therapies for Pulmonary Known or suspected pulmonary veno-occlusive disease Hypertension (COMPERA) registry. Among patients or pulmonary capillary hemangiomatosis with IPAH on any type of anticoagulant, the adjusted ¼ ¼ HR for survival was found to be 0.79 (95% CI, 0.66-0.94; FC functional class; WHO World Health Organization. See Table 1 legend for expansion of other abbreviation. P ¼ .007). For patients with the scleroderma-spectrum of disease and PAH (SSc-PAH), the use of SSRIs: One retrospective cohort study was identified anticoagulants was associated with a trend toward worse that assessed SSRI use in patients with PAH.35 Kawut survival (HR, 1.82; 95% CI, 0.94-3.54; P ¼ .08). et al35 found that use of SSRIs did not significantly improve survival outcomes (HR, 0.53; 95% CI, 0.07-3.9; Preston et al33 also conducted a retrospective cohort P ¼ .53). At this time, there is insufficient evidence to analysis using data from the Registry to Evaluate Early recommend for or against the use of SSRIs in patients And Long-term Pulmonary Arterial Hypertension with PAH. Disease Management (REVEAL) registry to assess the effect of warfarin anticoagulation on survival in IPAH Additional Considerations and SSc-PAH. In patients with IPAH, warfarin use was Despite the progress in medical therapy for PAH, there fi not signi cantly associated with survival (adjusted HR, are still a significant number of patients who do not ¼ 1.37; 95% CI, 0.84-2.25; P .17). Likewise, in patients adequately respond to—or who are unable to tolerate— fi with SSc-PAH, warfarin use was also not signi cantly maximal medical therapy. For these patients, lung or associated with better survival (adjusted HR, 1.60; heart-lung transplantation continues to be an important ¼ 95% CI, 0.84-3.06; P .15). therapeutic option that provides substantial The Kang et al study34 also assessed survival outcomes improvements in long-term survival and quality of life. associated with the use of warfarin among Korean Current guidelines from the International Society for patients with IPAH. They found that among the 31 Heart and Lung Transplantation recommend early included patients, warfarin use was associated with counseling about transplant and early referral to a better survival outcomes (HR, 0.21; 95% CI, 0.045-0.976; transplant program to minimize risks of delay of timely ¼ P .047). listing for transplantation for potential candidates These included studies could not be combined in meta- (Table 7). analysis because they were all relatively small, included Bilateral lung transplant is the most common transplant different classes of interventions, and had differing procedure for patients with PAH; however, heart-lung subpopulations. Because of the varying outcomes and transplantation may be required for patients with uncertainty of this intervention, the panel chose not to complex congenital disease and other considerations. make any recommendations at this time. Antiplatelet Agents: One randomized controlled trial Conclusions was identified that addressed the use of aspirin and Basic discovery, translational science, and clinical trials simvastatin in patients with PAH receiving continue to advance the treatment of patients with PAH. background therapy.36 No difference was found in the This document provides an evidence-based update primary outcome, 6MWD, between the aspirin and addressing important developments in the utilization of placebo group (0.5 m; 95% CI, 28.4 to 27.4 m). combination therapy, and consensus-based suggestions There is currently insufficient evidence to on the integration of palliative care and exercise training recommend for or against the use of antiplatelet (cardiopulmonary rehabilitation) into overall disease therapy for PAH. management. A treatment algorithm has been added to

584 Evidence-Based Medicine [ 155#3 CHEST MARCH 2019 ] assist the care provider in navigating the guidelines. 10. Atwood CW Jr, McCrory D, Garcia JG, Abman SH, Ahearn GS, American College of Chest Physicians. Pulmonary artery Dissemination and implementation efforts will follow. hypertension and sleep-disordered breathing: ACCP evidence-based Importantly, we continue to suggest early referral to clinical practice guidelines. Chest. 2004;126(1 suppl):72S-77S. expert centers and collaborative care using sound 11. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical clinical judgment. practice guidelines. Chest. 2004;126(1 suppl):78S-92S. 12. Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for Looking to the future, we strongly encourage the pulmonary arterial hypertension in adults: CHEST guideline and translation of basic discovery into safe and effective new expert panel report. Chest. 2014;146(2):449-475. therapies, through the conduct of well-designed clinical 13. Diekember RL, Ireland BK, Merz LR. Development of the Documentation and Appraisal Review Tool for systematic reviews. trials. World J Meta-Anal. 2015;3(3):142-150. 14. Higgins J, Altman D, Sterne J. Assessing risk of bias in included Acknowledgments studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Author contributions: All authors contributed equally to this Systematic Reviews of Interventions. Version 5.1.0 (updated March manuscript. 2011). The Cochrane Collaboration; 2011. https://training.cochrane. org/handbook. Accessed January 30, 2019. Financial/nonfinancial disclosures: See e-Table 6 for complete list of 15. American College of CHEST Physicans. 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